Medulloblastoma is the most common malignant brain tumor in children. Almost half the children who develop medulloblastoma die from it, and survivors often develop severe side effects as a result of the treatment. Improved approaches to treating medulloblastoma are likely to come from a deeper understanding of the cellular and molecular basis of the disease. One critical question about the etiology of medulloblastoma is the cell from which it originates. The morphology of tumor cells and their location on the surface of the cerebellum have led to speculation that the tumors arise from granule cell precursors (GCPs), restricted neural progenitors that give rise only to granule neurons. On the other hand, recent studies have shown that medulloblastomas express stem cell markers and can differentiate into both neurons and glia, suggesting that some of these tumors may arise from multipotent neural stem cells (NSCs). Cells with an NSC phenotype have also been suggested to represent cancer stem cells, cells that are resistant to conventional therapies and critical for the long-term growth and propagation of tumors in vivo. The cell of origin and the cancer stem cell may or may not be related, but identifying each of them has important implications for understanding and treating medulloblastoma. Our goal is to identify the cell of origin (tumor-initiating cell) and the cancer stem cell (tumor-propagating cell) for medulloblastomas resulting from mutations in the Sonic hedgehog-Patched signaling pathway. Humans with mutations in this pathway have an increased susceptibility to medulloblastoma. Moreover, patched mutant mice develop tumors that resemble human medulloblastoma, and represent a valuable model for the disease. Our preliminary studies suggest that the cell of origin in patched- associated tumors is a granule cell precursor, and that this cell type is required not only for tumor initiation but also for tumor propagation. We now propose to identify subsets of GCPs that are enriched for the ability to initiate tumors, and subsets of tumor cells that are uniquely capable of propagating tumors following transplantation. Identifying these cells will provide critical insight into the mechanisms of transformation, and will help us develop and test novel approaches to targeting medulloblastoma. PUBLIC HEALTH RELEVANCE: Identifying the cell of origin for medulloblastoma will allow us to compare tumor cells to their normal counterparts, so that key differences and vulnerabilities of tumor cells can be identified. In addition, recent studies suggest that cells resembling the cell of origin may persist in mature tumors (as cancer stem cells), and may be critical for propagating these tumors in vivo. Identifying these cells may allow us to develop more effective methods for eradicating the tumor.